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Multiple Endocrine Neoplasia Type 1 (MEN1) is a rare inherited endocrine tumor syndrome principally affecting parathyroid glands, neuroendocrine tissues of the gastro-entero-pancreatic and thoracic tracts, and anterior pituitary, caused by germline inactivating mutations of the MEN1 tumor suppressor gene. Primary hyperparathyroidism (PHPT) is usual...
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Background:
Primary hyperparathyroidism (pHPT) is the third most common endocrinopathy, affecting 1-3% of postmenopausal women, with a total incidence of 21.6 cases per 100,000 people in the adult population. This study aimed to analyze the oral health and related aspects of individuals with pHPT.
Material and methods:
A cross-sectional observat...
Purpose
This article reports on a 12-year follow-up of a Colombian family with a novel MEN1 gene variant (c.698dup, p.Met233IlefsTer4), identified through cascade genetic screening. The index case involved a rare type of tumor, an ACTH-secreting pancreatic neuroendocrine carcinoma.
Methods
The index case underwent MEN1 testing after presenting with...
Background
Multiple endocrine neoplasia (MEN1) is a rare inherited multi-tumour syndrome, affecting specific neuroendocrine organs and non-endocrine tissues with a variable spectrum of over 20 possible different combinations, caused by inactivating heterozygote mutations of the MEN1 gene.
Disease onset, penetrance, clinical presentation, course and...
Primary hyperparathyroidism is a relatively common endocrine disorder, which may be hereditary. This report describes clinical, biochemical, radiographic, and genetic findings, the latter obtained using next generation sequencing (NGS), in three consanguineous patients. Gene panels in NGS consisted of 5 or 70 genes, including MEN1 and RET. The firs...
Background: The surgical treatment of primary hyperparathyroidism (HPT) in patients with multiple endocrine neoplasia type 1 (MEN1) has evolved due the concern of permanent hypoparathyroidism. As the diagnosis has increased, the extent of operation has decreased. Most MEN1 patients requiring parathyroidectomy are younger than 50 years and they pose...
Citations
... Возможно, это связано с ранним началом заболевания. При этом восстановление данного показателя после хирургического лечения хуже [22], что создает предпосылки для обсуждения вопроса о проведении оперативного вмешательства до развития остеопороза [23]. Вместе с тем в настоящее время у пациента нет клинически манифестного ПГПТ (нормальный уровень кальция и паратгормона в сыворотке крови и отсутствие осложнений со стороны скелета и почек), что предполагает возможность консервативного наблюдения. ...
Multiple endocrine neoplasia type 1 (MEN1) and congenital adrenal hyperplasia (CAH) are rare monogenic hereditary endocrinopathies with a prevalence of 1–9 cases per 100,000 and 9–15 cases per 100,000, respectively. MEN1 is characterized by the development of multiple endocrine and nonendocrine organ tumors, including parathyroid, pituitary, and duodenopancreatic neuroendocrine tumors (NETs), which constitute the classical triad of the disease. CAH is associated with genetic defects in enzymes and transport proteins involved in the synthesis of adrenal cortical steroid hormones. Overall, cases of the combination of two hereditary diseases in one patient are extremely rare. In this article, we describe a clinical case of the combination of MEN-1 with all three classical components and CAH, which, taking into account the low prevalence of both diseases, represents scientific interest. To date, only one similar case has been described in the literature. In addition, the paper discusses the pathogenetically determined combination of CAH and Ehlers-Danlos syndrome, known as the CAH-X syndrome.
... The molecular diagnosis of MEN1 carriers has allowed the earlier diagnosis of MEN1-related tumors by periodic hormonal and radiologic screening (1,6,8,9,10,11). Therefore, young patients are predominantly asymptomatic at the time of pHPT diagnosis (1,2,6,9,11). ...
... The molecular diagnosis of MEN1 carriers has allowed the earlier diagnosis of MEN1-related tumors by periodic hormonal and radiologic screening (1,6,8,9,10,11). Therefore, young patients are predominantly asymptomatic at the time of pHPT diagnosis (1,2,6,9,11). Although parathyroidectomy (PTx) is the consensual treatment for MEN1-related pHPT (HPT/MEN1), the ideal timing to perform the operation in asymptomatic patients, especially in young individuals, remains under debate (2,11,12,13). ...
... Therefore, young patients are predominantly asymptomatic at the time of pHPT diagnosis (1,2,6,9,11). Although parathyroidectomy (PTx) is the consensual treatment for MEN1-related pHPT (HPT/MEN1), the ideal timing to perform the operation in asymptomatic patients, especially in young individuals, remains under debate (2,11,12,13). ...
Background: Potential influences of the parathyroidectomy (PTx) on quality of life (QoL) in multiple endocrine neoplasia type 1-related primary hyperparathyroidism (HPT/MEN1) are unknown.
Method: Short Form 36 Health Survey Questionnaire was prospectively applied in 30 HPT/MEN1 patients submitted to PTx (20, subtotal; 10, total with autograft), before, 6 and 12 months (mo.) after surgery. Parameters analyzed included QoL, age, HPT-related symptoms, general pain, comorbidities, biochemical/hormonal response, PTx type and parathyroid volume.
Results: Asymptomatic patients were younger (30 vs 38 years; p=0.04) and presented higher QoL scores (physical component score, PCS, 92.5 vs 61.2 p=0.0051; mental component score, MCS, 82.0 vs 56.0, p=0.04) than symptomatic ones. In both groups, QoL remained stable one year after PTx, independently of number of comorbidities. Preoperative general pain was negatively correlated with PCS (r =-0.60, p=0.0004) and MCS (r=-0.57, p=0.0009). Also, moderate/intense pain was progressively (6/12mo.) more frequent in cases developing hypoparathyroidism. The PTx type and hypoparathyroidism did not affect the QoL at 12mo. although remnant parathyroid tissue volume did have a positive correlation (p=0.0490; r=0.3625) to PCS 12mo. after surgery. Patients with 1-2 comorbidities had as pre-PTx PCS (p=0.0015) as 12mo. post-PTx PCS (p=0.0031) and MCS (p=0.0365) better than patients with 3-4 comorbidities.
Conclusion: A variable QoL profile was underscored in HPT/MEN1 reflecting multiple factors associated to this complex disorder as comorbidities, advanced age at PTx and presence of preoperative symptoms or of general pain perception. Our data encourage the early indication of PTx in HPT/MEN1 by providing known metabolic benefits to target-organs and avoiding potential negative impact on QoL.
... 13,[24][25][26]69 In addition, a study from Brazil reported a 42% prevalence of PanNETs in 19 patients with MEN1 age 12-20 103 13 Shariq et al. (2021) (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) of children with MEN1 already have manifestations at the paediatric age (although different age cut-offs are used). 13,[24][25][26]69,103,104 The wide range can partly be explained by different screening practices as Goudet et al. 24 found that 73% of those following a screening program <21 years had manifestations diagnosed at the paediatric age, while overall in their cohort this was only 17%. 24 Median age at first manifestation in the five cohorts was 14-17 years. ...
This review provides an overview of novel insights in the clinical management of patients with Multiple Endocrine Neoplasia Type 1, focusing on the last decade since the last update of the MEN1 guidelines. With regard to Diagnosis: Mutation-negative patients with 2/3 main manifestations have a different clinical course compared to mutation-positive patients. As for Primary hyperparathyroidism: subtotal parathyroidectomy is the initial procedure of choice. Current debate centers around the timing of initial parathyroidectomy as well as the controversial topic of unilateral clearance in young patients. For duodenopancreatic neuroendocrine tumors (NETs), the main challenge is accurate and individualized risk stratification to enable personalized surveillance and treatment. Thymus NETs remain one of the most aggressive MEN1-related tumors. Lung NETs are more frequent than previously thought, generally indolent, but rare aggressive cases do occur. Pituitary adenomas are most often prolactinomas and non-functioning micro-adenomas with an excellent prognosis and good response to therapy. Breast cancer is recognized as part of the MEN1 syndrome in women and periodical screening is advised. Clinically relevant manifestations are already seen at the pediatric age and initiating screening in the second decade is advisable. MEN1 has significant impact on QoL and US data show significant financial burden. In conclusion, patient outcomes have improved, but much is still to be achieved. For care tailored to the needs of the individual patient and improving outcomes on an individual basis, studies are now needed to define predictors of tumor behavior and effects of more individualized interventions. This article is protected by copyright. All rights reserved.
... If concomitant endocrinopathies are present, parathyroidectomy is recommended to be completed first. However, if an active insulinoma is present, hypoglycemia must first be cured and parathyroidectomy must therefore be postponed [50,51]. ...
Multiple endocrine neoplasia (MEN) is a group of heterogenous syndromes characterized by the occurrence of two or more endocrine gland tumors in a patient or related individuals in the same family. They are inherited in an autosomal dominant fashion and are highly penetrant. There are three types of MEN syndromes: MEN type 1 (MEN1), MEN type 2 (MEN2), and MEN type 4 (MEN4). MEN2 is further divided into MEN2A, MEN2B (formerly known MEN3), and familial medullary thyroid carcinoma (FMTC). Although MEN syndromes are rare, it is crucial to identify individuals at risk for potentially life-threatening neoplasias. This review article provides an update on each MEN syndrome, its genetics, diagnosis, and management in children.
... However, there is no consensus regarding the age at which screening should start, as the benefits are offset 70 by concerns about burden of testing, radiation exposure, and cost. 3 Moreover, some studies have indicated 71 that clinically-significant or symptomatic MEN1 manifestations are rare before 16 years of age, 4 although 72 it is of note that these reports consist of either small numbers of pediatric and adolescent patients from 73 single institutions, [5][6][7][8] or in the case of larger multi-center series, 9,10 include historical cohorts of patients 74 seen prior to the introduction of contemporary screening methods or in whom screening began relatively 75 late in childhood (Table 1). Thus, the incidence of MEN1-related manifestations in this age group is not 76 well-characterized, and may have been underestimated. ...
... Thus, the incidence of MEN1-related manifestations in this age group is not 76 well-characterized, and may have been underestimated. [4][5][6][7][8][9][10] Furthermore, there is also a lack of consensus 77 regarding the optimal management of MEN1 manifestations, such as PHPT and non-functioning pancreatic 78 neuroendocrine tumors (NF-PNETs), in children and adolescents. Our aims were therefore to evaluate the 79 occurrence of MEN1-related manifestations by ≤18 years of age, their treatment outcomes, and genotype- ...
Background:
Clinical manifestations and treatment outcomes in children and adolescents with multiple endocrine neoplasia type 1 are not well characterized.
Methods:
We conducted a retrospective cohort study of 80 patients with multiple endocrine neoplasia type 1 who commenced tumor surveillance at ≤18 years of age.
Results:
Fifty-six patients (70%) developed an endocrine tumor by age ≤18 years (median age = 14 years, range = 6-18 years). Primary hyperparathyroidism occurred in >80% of patients, with >70% undergoing parathyroidectomy, in which less-than-subtotal (<3-gland) resection resulted in decreased disease-free outcomes versus subtotal (3-3.5-gland) or total (4-gland) parathyroidectomy (median 27 months versus not reached; P = .005). Pancreaticoduodenal neuroendocrine tumors developed in ∼35% of patients, of whom >70% had nonfunctioning tumors, >35% had insulinomas, and <5% had gastrinomas, with ∼15% having metastases and >55% undergoing surgery. Pituitary tumors developed in >30% of patients, and ∼35% were macroprolactinomas. Tumor occurrence in male patients and female patients was not significantly different. Genetic analyses revealed 38 germline MEN1 mutations, of which 3 were novel.
Conclusion:
Seventy percent of children aged ≤18 years with multiple endocrine neoplasia type 1 develop endocrine tumors, which include parathyroid tumors for which less-than-subtotal parathyroidectomy should be avoided; pancreaticoduodenal neuroendocrine tumors that may metastasize; and pituitary macroprolactinomas.
... In adult patients this should not be postponed because bone complications are more severe in MEN1associated PHPT than in its sporadic counterpart (133). The published data with 19 MEN1 adolescents developing PHPT before age 20 years and undergoing parathyroidectomy before age 25 years to control calcemia support the use of surgery to avoid PHPT complications, even though 2 patients developed postsurgical hypoparathyroidism (134). Subtotal parathyroidectomy is always recommended. ...
Multiple Endocrine Neoplasia Type 1 (MEN1), a rare tumor syndrome that is inherited in an autosomal dominant pattern, is continuing to raise great interest for endocrinology, gastroenterology, surgery, radiology, genetics and molecular biology specialists. There have been two major clinical practice guidance papers that were published in the past two decades, with the most recent publication 8 years ago. Since then, several new insights on the basic biology and clinical features of MEN1 have appeared in the literature and those data are discussed in this review. The genetic and molecular interactions of the MEN1 encoded protein menin with transcription factors and chromatin modifying proteins in cell signaling pathways mediated by TGF-β/BMP, few nuclear receptors, Wnt/β-catenin and Hedgehog (Hh), and preclinical studies in mouse models have facilitated the understanding of the pathogenesis of MEN1-associated tumors and potential pharmacological interventions. The advancements in genetic diagnosis have offered a chance to recognize MEN1 related conditions in germline MEN1 mutation negative patients. There is a rapidly accumulating knowledge about clinical presentation in children, adolescents and pregnancy that is translatable into the management of these very fragile patients. The discoveries about the genetic and molecular signatures of sporadic neuro-endocrine tumors support the development of clinical trials with novel targeted therapies, along with advancements in diagnostic tools and surgical approaches. Finally, quality of life studies in patients affected by MEN1 and related conditions represent an effort necessary to develop a pharmacoeconomic interpretation of the problem. Because advances are being made both broadly and in focused areas, this timely review presents and discusses those studies collectively.
... Contrasting with a high penetrance of HPT/MEN1 at 20 y (50-60%), PTX has been conducted in a few MEN1 adolescents (27)(28)(29) probably because cases are predominantly asymptomatic and the ideal timing to indicate surgery for HPT/MEN1 remains undefined being more debatable in this age group yet (29) As a specific guideline for very young MEN1 cases are still lacking, the indication for PTX in affected adolescents should take in account several aspects that are characteristic of this age group, as be cautious with and to avoid the possible prejudice of bone accretion and peak of bone mass in early life. In addition, hypothyroidism should be avoided to allow normal growth (6). ...
... In a subsequent report of the same group with 14 cases diagnosed during second decade of life and operated for HPT before 25 years, most cases had TPTX-AG (eight cases) and two of them were hypocalcemic in last follow-up. Conversely, none of their four cases submitted to less extensive procedures (partial parathyroidectomy) had hypocalcemia (29). However, in half of this latter group, a second partial surgery was performed due recurrent HPT from three up to 14 years after first surgery and in one they performed a TPTX-AG after persistent disease. ...
... However, in half of this latter group, a second partial surgery was performed due recurrent HPT from three up to 14 years after first surgery and in one they performed a TPTX-AG after persistent disease. They had only one recurrence in autograft in case who underwent TPTX-AG (29). In our study, within four young cases who underwent to U-LSTPTX, two remain normocalcemic four and 14 years after surgery and other two had recurrence after 8 years, one of them needing of second surgical procedure while other follows with mild HPT 16 years after PTX. ...
Background: The surgical treatment of primary hyperparathyroidism (HPT) in patients with multiple endocrine neoplasia type 1 (MEN1) has evolved due the concern of permanent hypoparathyroidism. As the diagnosis has increased, the extent of operation has decreased. Most MEN1 patients requiring parathyroidectomy are younger than 50 years and they pose a difficult balance to achieve between persistent HPT and life-long hypoparathyroidism. The aim of the present study is to review our experience with a large series of patients with MEN1-related HPT (HPT/MEN1) treated at a single institution in order to find clues to a better treatment decision in these younger cases.
Method: Retrospective analysis of consecutive HPT/MEN1 cases treated at a single institution with different operations: total parathyroidectomy and immediate forearm autograft (TPTX-AG), subtotal (STPTX), unintentional less than subtotal (U-LSTPTX) and intentional less than subtotal parathyroidectomy (I-LSTPTX).
Results: Considering 84 initial cases operated on since 2011 (TPTX-AG, 39; STPTX, 22, U-LSTPTX, 13, and I-LSTPTX, 10), the rates of hypoparathyroidism were 30.8% (U-LSTPTX), 28.2% (TPTX-AG), 13.6% (STPTX), and 0% (I-LSTPTX). Two-thirds of them (68%; 57/84) were young (<50 years) or asdolescents. MIBI scan was more sensitive to show parathyroid glands and bilateral disease. Considering the concordance of MIBI and ultrasound for the possibility of unilateral clearance, it would be suitable to 22.6% of the cases. Intra-operative parathormone showed a significant decay even after unilateral exploration, but longer follow up is necessary. Overall, there were seven (4%) adolescents in 161 cases treated from 1987 to 2018, three underwent TPTX-AG and four had U-LSTPTX. Five are euparathyroid, one had mild recurrence, and one required a reoperation after 8 years due to the residual gland.
Conclusions: Young patients are the most frequent candidates to parathyroidectomy. Less extensive procedures may be planned only if carefully reviewed preoperative imaging studies suggest a localized disease. Patients and their relatives should be fully informed of the risks and benefits during consent process. Future research with larger cohorts and long-term results are necessary to clarify if less than I-LSPTX or unilateral clearance are really adequate in selected groups of patients with HPT/MEN1 presenting lower volume of disease detected by preoperative imaging studies.
In 1953, for the first time, Paul Wermer described a family presenting endocrine gland neoplasms over several generations. The transmission was autosomal dominant and the penetrance was high. Forty years later in 1997, the Multiple Endocrine Neoplasia type 1 (MEN1) gene was sequenced, thus enabling diagnosis and early optimal treatment.
Patients carrying the MEN1 gene present endocrine but also non-endocrine tumors. Parathyroid, pancreatic and pituitary impairment are the three main types of endocrine involvement.
The present article details therapeutic management of hyperparathyroidism, neuroendocrine pancreatic tumors and pituitary adenomas in patients carrying the MEN1 gene. Significant therapeutic progress has in fact been made in the last few years.
As concerns the parathyroid glands, screening of family members and regular monitoring of affected subjects now raise the question of early management of parathyroid lesions and optimal timing of parathyroid surgery.
As concerns the duodenum-pancreas, proton-pump inhibitors are able to control gastrin-secreting syndrome, reducing mortality in MEN1 patients. Mortality in MEN1 patients is no longer mainly secondary to uncontrolled hormonal secretion but to metastatic (mainly pancreatic) disease progression. Tumor risk requires regular monitoring of morphological assessment, leading to iterative pancreatic surgery in a large number of patients.
Finally, pituitary adenomas in MEN1 patients are traditionally described as aggressive, invasive and resistant to medical treatment. However, regular pituitary screening showed them to be in fact infra-centimetric and non-secreting in the majority of patients.
Consequently, it is necessary to regularly monitor MEN1 patients, with regular clinical, biological and morphological work-up. Several studies showed that this regular monitoring impairs quality of life. Building a relationship of trust between patients and care provider is therefore essential. It enables the patient to be referred for psychological or psychiatric care in difficult times, providing long-term support and preventing any breakdown in continuity of care.
